The transplant program at the University of Pennsylvania (UP)has had a long-standing interest in the application of pancreatic islet transplantation in the treatment of diabetes mellitus. The program has continued basic investigations of the biological barriers to islet transplantation, with emphasis on the induction of immunological tolerance. Insights gained from experimental islet transplantation have led to recent successful applications of this therapy and achievement of euglycemia in patients with Type I diabetes mellitus. Based on these advances, a comprehensive islet transplantation program was established at the UP integrating a multidisciplinary team of investigative scientists and clinicians with recognized expertise in diabetes research and transplantation. Since the inception of the program in 1999, significant progress has been made in building its critical components: 1) construction of an Food and Drug Administrative (FDA)-compliant current good manufacturing practices (cGMP) facility devoted exclusively to islet processing; 2) recruitment and training of personnel qualified to perform islet isolation and assignment of dedicated transplant surgeons for on-site recovery of cadaveric pancreata; 3) establishment of a strong collaboration with the local organ procurement organization, which has led to a marked increase in the procurement of the human cadaveric pancreata; 4) distribution of isolated pancreatic islets to regional and national investigators engaged in diabetes research; and 5) development of a standardized islet quality index. In the present application, this strong infrastructure will serve as the mechanism for increasing the availability of human cadaveric pancreata suitable for preparation of isolated islets. This goal will be accomplished by procurement of pancreata from an expanded donor pool, including non-heart-beating organ donors. Another emphasis for the program will be the refinement of the islet quality index, based on physiological, biochemical, and morphological parameters, for correlation with the outcome of islet transplantation. With this strong platform in place, the program is poised to realize its goal of generating large quantities of highly purified and quality-controlled human islets for transplantation into Type I insulin-dependent diabetic patients.